Dario Vignali, Ph.D.

  • Interim Chair and Distinguished Professor of Immunology
  • Frank Dixon Chair in Cancer Immunology
  • Co-Director, Cancer Immunology Training Program (CITP)
  • Department of Immunology, University of Pittsburgh School of Medicine
  • Associate Director for Scientific Strategy and Co-Leader of the Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center

Education & Training

  • B.S., East London University-Immunology/Medical Microbiology, 1985
  • Ph.D., London School of Hygiene and Tropical Medicine-Immunology of Infectious Diseases, 1988

Research Interest Summary

Systems immunology approaches to dissect transcriptional networks and identify novel mechanism of immune control in cancer and autoimmunity using sophisticated mouse models and samples from cancer patients.

Research Categories

Research Interests

Our research focuses on gaining a better understanding of the inhibitory mechanisms, including inhibitory receptors and regulatory T cells, that limit anti-tumor immunity in cancer and are insufficient in autoimmune disease.  We also have discovery-based programs aimed at identifying novel targets for therapeutic intervention.  We are also working with UPMC Hillman Cancer Center scientists and clinicians to facilitate the translation of novel therapeutic modalities with a focus on immunologically impacted solid tumors (primarily head and neck, melanoma, lung, ovarian, breast). Our research focuses on various aspects of T cell function, combining several project and disease areas:

(1) Mechanistic Focus:

   (a) Immune Regulation - Regulatory T cells (Tregs): Identification of novel Treg molecules & their function; mechanism of Treg function; regulation of Treg fragility & stability via NRP1 & other pathways; IL-35 signaling & mechanism of action; novel Ebi3 binding partners; IL-10 & IFNg function; neuron-immune interactions.
   (b) Immune Regulation - Inhibitory Molecules: Identification of novel inhibitory receptors (IR) and their mechanisms; immune modulation of T cell subsets by LAG3, PD1 and NRP1; PD1-LAG3 synergy; mechanism of CD8+ and CD4+ T cell exhaustion; protein engineering to develop novel therapeutics.
   (c) Structure-function analysis of T cell receptor (TCR):CD3 complex and LAG3 signaling: Mechanism of TCR:CD3 signaling; modulation & control of TCR signaling by IRs.
   (d) Systems Immunology: Single cell systems approaches (transcriptomic & epigenomic) to hypothesis test, hypothesis generate and discover; technology and algorithm development; multispectral imaging.

(2) Disease Focus:

  (a) Cancer: Biology of LAG3/PD1, IL-35 and NRP1 in mouse models of cancer & also in samples from treatment-naive patients or immunotherapy recipients; primary focus on solid tumors – head & neck, melanoma, lung, ovarian cancer, breast, with some work on pancreatic, GI & glioma cancers, & pediatric solid malignancies; novel approaches for therapeutic translation; biomarker discovery.
  (b) Autoimmune and Inflammatory Disease: Impact, function & insufficiency of Tregs & IRs in several autoimmune & inflammatory disease with emphasis on models of autoimmune diabetes (NOD), EAE & asthma; development of therapeutic approaches (enhance Treg stability; IR agonists).

Representative Publications

Huang C-T, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Lavitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DAA (2004). Role of LAG-3 in regulatory T cells. Immunity 21:503-13 [PMID: 15485628].

Li N, Wang Y, Forbes K, Vignali KM, Heale BS, Saftig P, Hartmann D, Black R, Rossi JJ, Blobal C, Dempsey PJ, Workman CJ, Vignali DAA (2007). Metalloproteases regulate T cell proliferation and effector function via LAG-3. EMBOJ 26: 494-504 [PMCID:1783452].

Woo S-R*, Turnis ME*, Goldberg MV*, Bankoti J, Selby M, Nirschl CJ, Bettini ML, Vogel P, Liu C-L, Tangsombatvisit S, Grosso JF, Netto G, Smeltzer MP, Chaux A, Utz PJ, Workman CJ, Pardoll DM, Korman AJ, Drake CG, Vignali DAA (2012). Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T cell function to promote tumoral immune escape. Cancer Research 72:917-927 [PMCID: 3288154].

Zhang Q, Chikina M, Szymczak-Workman AL, Horne W, Kolls JK, Vignali KM, Normolle D, Bettini M, Workman CJ, Vignali DAA (2017). LAG-3 limits regulatory T cell proliferation and function in autoimmune diabetes. Science Immunology. 2:eaah4569 [Not yet listed in PubMed].

Collison LW, Workman CJ, Kuo TK, Boyd K, Wang Y, Vignali K, Cross R, Sehy D, Blumberg RS, Vignali DAA (2007). The inhibitory cytokine IL-35 contributes to regulatory T cell function. Nature 450: 566-569 [PMID: 18033300].

Collison LW, Chaturvedi V, Henderson AL, Giacomin PR, Guy C, Bankoti J, Finkelstein D, Forbes K, Workman CJ, Brown SA, Rehg JE, Jones ML, Ni H-T, Artis D, Turk MJ, Vignali DAA (2010). Interleukin-35 mediated induction of a potent regulatory T cell population. Nature Immunology 11:1093-1101 [PMCID: 3008395].

Collison LC*, Delgoffe GM*, Guy C, Vignali KM, Chaturvedi V, Fairweather D, Satoskar AR, Garcia KC, Hunter CA, Drake CG, Murray PJ, Vignali DAA (2012). The composition and signaling of the IL-35 receptor are unconventional. Nature Immunology 13:290-299 [PMCID: 3529151].

Turnis ME*, Sawant DV*, Szymczak-Workman A, Andrews LP, Delgoffe GM, Yano H., Beres AJ, Vogel P, Workman CJ, Vignali DAA (2015). Interleukin-35 limits anti-tumor immunity. Immunity. 44:316-29 [PMCID: 4758699].

Collison LW, Pillai MR, Chaturvedi V, Vignali DAA (2009). Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner. J. Immunol. 182:6121-6128 [PMID:19414764; PMCID: 2698997].

Delgoffe GM*, Woo S-R*, Turnis ME, Gravano DM, Guy C, Overacre AE, Bettini ML, Vogel P, Finkelstein D, Bonnevier J, Workman CJ, Vignali DAA (2013). Stability and function of regulatory T cells is maintained by a neuropilin-1:semaphorin-4a axis. Nature 501:252-256 [PMCID: 3867145].

Overacre-Delgoffe AE, Chikina M, Dadey RE, Yano H, Brunazzi EA, Shayan G, Horne W, Moskovitz JM, Kolls JK, Sander C, Shuai Y, Normolle DP, Kirkwood J, Ferris RL, Delgoffe GM, Bruno TC, Workman CJ, Vignali DAA (2017). Interferon-g drives Treg fragility to promote anti-tumor immunity. Cell 169:1130-1141 [PMCID:5509332].

Sawant DV*, Yano H*, Chikina M, Zhang Q, Liao M, Liu C, Sun Z, Sun T, Tabib T, Pennathur A, Luketich JD, Lafyatis R, Chen W, Poholek A, Bruno TC, Workman CJ, Vignali DAA (2019).  Adaptive plasticity of IL10+ and IL35+ regulatory T cells cooperatively promote intratumoral T cell exhaustion. Nature Immunology 20:724-735 [PMID: 30936494; PMCID: 6531353; DOI: 10.1038/s41590-019-0346-9].

Liu C, Chikina M, Deshpande R, Menk AV, Wang T, Tabib T, Brunazzi EA, Vignali KM, Sun M, Stolz DB, Lafyatis RA, Chen W, Delgoffe GM, Workman CJ, Wendell SG, Vignali DAA (2019).  Treg cells promote the SREBP1-dependent metabolic fitness of M2-like intratumoral macrophages via CD8+ T cells. Immunity 51:381-397 [PMID: 31350177; PMCID: 6703933; DOI: 10.1016/j.immuni.2019.06.017].

Cillo AR, Kürten C, Tabib T, Qi Z, Onkar S, Wang T, Liu L, Duvvuri U, Kim S, Soose RJ, Oesterreich S, Chen W, Lafyatis R, Bruno TC†, Ferris RL†, Vignali DAA† (2020).  Immune landscape of viral- and carcinogen-driven head and neck cancer. Immunity 52:183-199 [PMID: 31924475; PMCID: 7201194; DOI: 10.1016/j.immuni.2019.11.014].

Liu C, Somasundaram A, Manne S, Gocher AM, Szymczak-Workman AL, Vignali KM, Scott EN, Normolle DP, Wherry EJ, Lipson EJ, Ferris RL, Bruno TC, Workman CJ, Vignali DAA (2020). Neuropilin-1 is a T cell memory checkpoint limiting long-term anti-tumor immunity. Nature Immunology 21:1010-1021 [PMID: 32661362; PMCID: 7442600; DOI: 10.1038/s41590-020-0733-2].

Andrews LP, Somasundaram A, Moskovitz JM, Szymczak-Workman AL, Liu C, Cillo AR, Lin H, Normolle DP, Moynihan KD, Taniuchi I, Irvine DJ, Kirkwood JM, Lipson EJ, Ferris RL, Bruno TC, Workman CJ, Vignali DAA (2020). Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding.  Science Immunology 5:eabc2728 [PMID: 32680952; PMCID: 7901539; DOI: 10.1126/sciimmunol.abc2728].

Andrews LA, Vignali KM, Szymczak-Workman AL, Burton AR, Brunazzi EA, Ngiow SF, Harusato A, Sharpe AH, Wherry EJ, Taniuchi I, Workman CJ, Vignali DAA (2021). A Cre-driven allele-conditioning line to interrogate CD4+ conventional T cells.  Immunity 54:2209-2217 [PMID: 34551314; DOI: 10.1016/j.immuni.2021.08.029; Free Article].

Chuckran CA, Cillo AR, Moskovitz J, Overacre-Delgoffe A, Somasundaram AS, Magnon GC, Abecassis I, Zureikat AH, Luketich J, Pennathur A, Sembrat J, Rojas M, Merrick DT, Taylor SE, Orr B, Modugno F, Bukanovich R, Schoen RE, Kim S, Duvvuri U, Zeh H, Edwards R, Kirkwood JM, Coffman L, Ferris RL, Bruno TC, Vignali DAA (2021).  Neuropilin-1 Enforces Human Regulatory T cell Stability and Function in Solid Tumors.  Science Translational Medicine 13:eabf8495 [PMID: 34878821; PMCID: 9022491; DOI: 10.1126/scitranslmed.abf8495].

Cillo AR, Somasundaram A, Shan F, Cardello C, Workman CJ, Kitsios GD, Ruffin A, Kunning S, Lampenfeld C, Onkar S, Grebinoski S, Deshmukh G, Methe B, Liu C, Nambulli S, Andrews L, Duprex WP, Joglekar A, Benos PV, Ray P, Ray A, McVerry BJ, Zhang Y, Lee JS, Das J, Singh H, Morris A, Bruno TC, Vignali DAA (2021). Bifurcated monocyte states predictive of mortality outcomes in severe COVID-19. Cell Reports Medicine 2:100476 [PMID: 34873589; PMCID: 8636386; DOI: 10.1016/j.xcrm.2021.100476].

Guy C, Mitrea DM, Chou P-C, Temirov J, Vignali KM, Liu X, Zhang H, Kriwacki R, Bruchez M, Watkins S, Workman CJ†, Vignali DAA† (2022). LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation. Nature Immunology 23:757-767 [PMID: 35437325; PMCID: 9106921; DOI: 10.1038/s41590-022-01176-4].

Grebinoski S*, Zhang Q*, Cillo AR, Manne S, Burnazzi EA, Tabib T, Cardello C, Lian C, Murphy GF, Lafyatis R, Wherry EJ, Das J, Workman CJ, Vignali DAA (2022). Autoreactive CD8+ T cells are restrained by a divergent exhaustion program. Nature Immunology 23:868-877 [PMID: 35618829; PMCID: 9179227; DOI: 10.1038/s41590-022-01210-5; UPMC: https://inside.upmc.com/tapping-restrained-t-cells-could-hold-potential-... ].

Cillo AR, Mukherjee E, Bailey N, Onkar S, Daley J, Salgado C, Li X, Liu D, Ranganathan S, Burgess M, Sembrat J, Weiss K, Watters R, Bruno TC*, Vignali DAA*, Bailey KM* (2022). Ewing sarcoma and osteosarcoma have distinct immune signatures and intercellular communication networks. Clinical Cancer Research 28:4968-4982 [PMID: 36074145; PMCID: 9669190; DOI: 10.1158/1078-0432.CCR-22-1471].

Onkar SS, Cui J, Zou J, Cardello C, Cillo AR, Uddin MR, Sagan A, Joy M, Osmanbeyoglu HU, Pogue-Geile K, McAuliffe P, Lucas PC, Tsang GC, Lee AV, Bruno TC, Oesterreich S*, Vignali DAA* (2022). Immune landscape in invasive ductal and lobular breast cancer reveals a divergent macrophage-driven microenvironment. Nature Cancer 4: 516–534 [PMID: 36927792; PMCID: Pending; DOI: 10.1038/s43018-023-00527-w].

Gocher-Demske AM, Cui J, Szymczak-Workman AL, Vignali KM, Latini JN, Pieklo GP, Kimball, JC, Avery L, Cipolla WL, Huckenstein BR, Hedden L, Meisel M, Alcorn JF, Kane LP, Workman CJ, Vignali DAA (2023).  Interferon gamma-induction of TH1-like regulatory T cells controls anti-viral responses. Nature Immunology 24: 841-854 [PMID: 36928412; PMCID: Pending; DOI: 10.1038/s41590-023-01453-w].

Shan F, Cillo AR, Cardello C, Yuan D, Kunning SR, Cui J, Lampenfeld C, Williams AM, McDonough AP, Pennathur A, Luketich JD, Kirkwood JM, Ferris RL, Bruno TC, Workman CJ, Benos PV, Vignali DAA (2023). Integrated BATF transcriptional network regulates suppressive intratumoral regulatory T cells. Science Immunology, in press.

Full List of Publications